Abstract
Diabetes in whites of European descent with hemochromatosis was first attributed to pancreatic siderosis. Later observations revealed that the pathogenesis of diabetes in HFE hemochromatosis is multifactorial and its clinical manifestations are heterogeneous. Increased type 2 diabetes risk in HFE hemochromatosis is associated with one or more factors, including abnormal iron homeostasis and iron overload, decreased insulin secretion, cirrhosis, diabetes in first-degree relatives, increased body mass index, insulin resistance, and metabolic syndrome. In p.C282Y homozygotes, serum ferritin, usually elevated at hemochromatosis diagnosis, largely reflects body iron stores but not diabetes risk. In persons with diabetes type 2 without hemochromatosis diagnoses, serum ferritin levels are higher than those of persons without diabetes, but most values are within the reference range. Phlebotomy therapy to achieve iron depletion does not improve diabetes control in all persons with HFE hemochromatosis. The prevalence of type 2 diabetes diagnosed today in whites of European descent with and without HFE hemochromatosis is similar. Routine iron phenotyping or HFE genotyping of patients with type 2 diabetes is not recommended. Herein, we review diabetes in HFE hemochromatosis and the role of iron in diabetes pathogenesis in whites of European descent with and without HFE hemochromatosis.
Highlights
The prevalence of diabetes decreased among hemochromatosis case series published in the interval 1935–1998 (Figure 1)
In HFE hemochromatosis, excessive iron absorption and increased iron stores are due to lack of hepcidin upregulation, mutations in nonHFE genes may act as positive “modifiers” of iron absorption in some p.C282Y homozygotes [19, 25, 26]
serum ferritin (SF) levels were positively associated with fasting glucose [81]; impaired glucose metabolism [77]; insulin levels [81]; prediabetes [75]; and diabetes [73, 76,77,78, 82,83,84,85] in crosssectional studies of participants unselected for hemochromatosis diagnoses
Summary
The prevalence of diabetes decreased among hemochromatosis case series published in the interval 1935–1998 (Figure 1). Earlier diagnosis of hemochromatosis due to iron phenotyping in probands and family members and subsequent phlebotomy therapy could partly explain the decrease. In two nonscreening hemochromatosis case series published in 2006 and 2008, respectively [1, 2], the prevalence of diabetes was lower than reported in the 20th C. Earlier diagnosis of hemochromatosis due to iron phenotyping of probands and family members and their subsequent phlebotomy therapy to achieve iron depletion could partly explain this decrease. The widespread adoption of HFE genotyping to enhance hemochromatosis diagnosis after 1996 could partly explain the further decline in cirrhosis prevalence in nonscreening hemochromatosis index patients reported in 2000 [3] (Figure 3). The proportion of p.C282Y homozygotes identified in population screening who had biopsy-proven cirrhosis was lower than that observed in nonscreening settings but is typically higher than in control subjects (Figure 4)
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